ART Guidelines

ART Guidelines


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  • ABBREVIATIONS
    /r ritonavir-boosted
    3TC lamivudine
    ABC abacavir
    ADR adverse drug reaction
    AKI acute kidney injury
    ALT alanine transaminase
    ANC antenatal care
    ART antiretroviral therapy
    ARV antiretroviral
    AST aspartate transaminase
    ATV atazanavir
    ATV/r ritonavir-boosted atazanavir
    AZT zidovudine
    bd twice daily
    CD4+ cluster of differentiation 4
    CM cryptococcal meningitis
    CNS central nervous system
    CrAg cryptococcal antigen
    CrCl creatinine clearance rate
    CSF cerebrospinal fluid
    CTX cotrimoxazole
    d4T stavudine
    ddI didanosine
    DILI drug-induced liver injury
    DNA deoxyribonucleic acid
    DRV darunavir
    DRV/r ritonavir-boosted darunavir
    DTG dolutegravir
    eGFR estimated glomerular filtration rate
    ELISA enzyme-linked immunosorbent assay
    ETR etravirine
    FBC full blood count
    FTC emtricitabine
    GI gastrointestinal
    Hb haemoglobin
    HBsAg hepatitis B surface antigen
    HBV hepatitis B virus
    HIV human immunodeficiency virus
    ICU intensive care unit
    INH isoniazid
    INR international normalised ratio
    InSTI integrase strand transfer inhibitor
    IPT isoniazid preventive therapy
    IRIS immune reconstitution inflammatory syndrome
    LAM lipoarabinomannan
    LDL-C low-density lipoprotein cholesterol
    LFT liver function test
    LP lumbar puncture
    LPV lopinavir
    LPV/r ritonavir-boosted lopinavir
    MDRD modification of diet in renal disease
    MTCT mother-to-child transmission of HIV
    MVC maraviroc
    NGT nasogastric tube
    NNRTI non-nucleoside reverse transcriptase inhibitor
    NRTI nucleoside reverse transcriptase inhibitor
    NTDs neural-tube defects
    NtRTI nucleotide reverse transcriptase inhibitor
    NVP nevirapine
    OI opportunistic infection
    PAS p-aminosalicylic acid
    PCR polymerase chain reaction
    PI protease inhibitor
    PI/r ritonavir-boosted protease inhibitor
    PMTCT prevention of mother-to-child transmission of HIV
    PPIs proton pump inhibitors
    PrEP pre-exposure prophylaxis
    QTc corrected QT interval
    RAL raltegravir
    RCTs randomised controlled trials
    RIF rifampicin
    RFB rifabutin
    RNA ribonucleic acid
    RPV rilpivirine
    RTV or /r ritonavir
    sCr serum creatinine
    sCrAg serum cryptococcal antigen
    TAF tenofovir alafenamide
    TAM thymidine analogue mutation
    TB tuberculosis
    TB-IRIS tuberculosis immune reconstitution inflammatory syndrome
    TBM tuberculosis meningitis
    TC total cholesterol
    TDF tenofovir disoproxil fumarate
    TG triglycerides
    TST tuberculin skin test
    UDP uridine 5’-diphospho
    ULN upper limit of normal
    VL viral load
    WHO World Health Organization
    WOCP women of childbearing potential








    Management of patients starting or currently receiving second-line therapy
            Key points
     
    • When DTG is used in second-line therapy, there should be at least one fully active accompanying drug until further evidence is available.
    • If the patient is failing an NNRTI regimen with 3TC/FTC + either TDF or ABC, then AZT + 3TC + DTG is the recommended second-line regimen.
    • If the patient is failing other first-line regimens, then resistance testing is advised to decide on the choice of NRTIs in a DTG-based second-line regimen.
    • Boosted PI + two NRTI second-line regimens are effective even if there is resistance to both NRTIs in the regimen.
    • We advise DRV/r 800 mg/100 mg once daily as the first choice PI for use in second-line therapy.

    Recommendations for patients failing a first-line regimen
    Failed first-line regimen of two NRTIs + NNRTI

    Table 14 summarises the recommended second-line regimen to start in patients who have failed a first-line regimen consisting of two NRTIs + NNRTI.
     

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    TABLE 14: Recommended second-line regimen in patients who have failed a first-line regimen of two NRTIs + NNRTI.
    Failing first-line regimen Advised second-line regimen
    TDF + 3TC (or FTC) + NNRTI AZT + 3TC + DTG
    AZT + 3TC + NNRTI Resistance test – if fully active NRTI is available, then combine this with: 3TC (or FTC) + DTG; or TDF + FTC + DRV/r
    ABC + 3TC + NNRTI AZT + 3TC + DTG

    3TC, lamivudine; AZT, zidovudine; ABC, abacavir; DTG, dolutegravir; FTC, emtricitabine; DRV/r, ritonavir-boosted darunavir; NNRTI, non-nucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; TDF, tenofovir disoproxil fumarate.
    †, If the patient has chronic hepatitis B, then continue TDF, in addition, in the second-line regimen.
    ‡, Provided that the patient has not potentially previously experienced virological failure on TDF, and has not experienced TDF nephrotoxicity previously.


    Based on the results of the DAWNING trial, it is preferable to use a DTG-based regimen rather than a PI/r regimen in second-line therapy.17 In this trial, a second-line regimen of DTG + two NRTIs was superior in terms of virological suppression and better tolerated than LPV/r + two NRTIs in patients who had failed a first-line regimen of NNRTI + two NRTIs. An important caveat is that all patients enrolled in this trial had a resistance test performed at entry and had to have at least one fully active NRTI to be eligible. Thus, the current evidence supports a DTG-based regimen in second-line ART only when used with at least one fully active NRTI. Whether a DTG-based second-line regimen would be equally effective with two NRTIs when there is resistance to both those NRTIs is currently a knowledge gap that is being addressed by several clinical trials – we do not advise such a strategy until the results of those trials are available.

    In patients failing a first-line regimen in which the NRTIs are TDF + 3TC (or FTC), the mutations selected are typically M184V by 3TC (or FTC) and K65R (or K70E) by TDF. None of these mutations compromise AZT; in fact they render the virus hyper-susceptible to it. Therefore, in this scenario, AZT remains fully active, and we can infer from the DAWNING trial results that a second-line regimen of AZT + 3TC + DTG will be optimally effective. The same applies for patients failing an ABC + 3TC + NNRTI regimen: AZT retains susceptibility and can be used with 3TC and DTG in a second-line regimen.

    Where patients have failed an AZT (or d4T) + 3TC + NNRTI regimen, this could have resulted in the accumulation of thymidine analogue mutations (TAMs) and M184V. Certain TAMs compromise TDF, meaning that it is unpredictable whether there is a fully active NRTI if a regimen of TDF + 3TC (or FTC) + DTG is used in second-line therapy. We therefore advise resistance testing in such patients. If the resistance test demonstrates a fully active NRTI, then that NRTI can be used with 3TC (or FTC) + DTG in the second-line regimen. If there is no fully active NRTI or a resistance test is not possible in this situation (e.g. public sector), then we recommend a regimen of TDF + 3TC (or FTC) + DRV/r. The reason for this is that boosted PI + two compromised NRTIs retains activity as a second-line regimen (see below).

    WOCP must be counselled about the potential risk and benefits of DTG and be allowed to make an informed decision regarding the use of DTG and contraception. If such patients choose not to use DTG in second-line therapy, then DRV/r should be used in its place.

    Failed first-line regimen of two NRTIs + dolutegravir

    The second-line regimen to commence in patients who have failed a first-line approach of two NRTIs + DTG is provided in Table 15.
     

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    TABLE 15: Recommended second-line regimen in patients who have failed a first-line regimen of two NRTIs + dolutegravir.
    First-line regimen failing Second-line regimen advised
    Two NRTIs + DTG Only switch to second-line if resistance test shows DTG resistance, and second-line should be two NRTIs (selected based on resistance test) + DRV/r.
    DTG, dolutegravir; DRV/r, ritonavir-boosted darunavir; NRTI, nucleoside reverse transcriptase inhibitor. 


    If patients experience virological failure on a first-line DTG-based regimen, then we do not recommend switching to second-line therapy unless a resistance test is performed and demonstrates DTG resistance. This is because DTG is a very robust drug and resistance is very rare when used in triple-drug combination first-line therapy. Therefore, it is far more likely that a VL > 50 copies/mL is attributed to adherence problems rather than resistance. If DTG resistance is demonstrated, then we advise a regimen of two NRTIs + DRV/r, with the two NRTIs selected based on the resistance test results.

    Patients currently established on protease inhibitor-based second-line therapy
    Viral load < 50 copies/mL

    Clinicians can consider switching of patients currently on a second-line PI/r regimen, to a DTG regimen, particularly in patients experiencing GI side-effects of PIs. This switch may also simplify the regimen and reduce pill burden. However, before such a switch is made, we advise a careful review of the treatment and resistance (genotype test) history to ensure that there is at least one fully active NRTI to accompany DTG in the new regimen. If this cannot be assured, then we advise maintaining the current PI/r regimen – though a switch to an alternative PI/r can be considered to improve tolerance. If continuing a PI is not possible, then a switch to a DTG-based second-line regimen without an assured active NRTI could be considered with close VL monitoring. Refer to Table 16 for our advice when considering switching a patient on a PI/r-based regimen to DTG in second-line therapy where the VL < 50 copies/mL.
     

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    VL > 50 copies/mL

    In patients on a second-line regimen containing a boosted PI, if the VL is not suppressed, then we do not advise switching to DTG. We advise enhanced adherence counselling and switching to an alternative boosted PI if there is intolerance. If the VL subsequently re-suppresses to an undetectable VL < 50 copies/mL, then the advice in Module 11 should be followed. If the VL remains elevated, then the patient may be eligible for a resistance test, with consideration for third-line therapy if they fulfil the criteria outlined in Module 14.
     

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    BOX 3: Boosted protease inhibitor + two NRTIs is an option in second-line therapy even if there is resistance to both NRTIs.

    Because boosted PIs are robust drugs (i.e. resistance develops slowly) in PI-naive patients, it is very likely that virological suppression will be achieved with good adherence, even if the two NRTIs used in second-line therapy are compromised by NRTI resistance mutations. This is supported by findings of the EARNEST (Europe-Africa Research Network for Evaluation of Second-line Therapy)60, SELECT (‘Second-Line Effective Combination Therapy’ in resource-limited settings)61 and SECOND-LINE72 trials, which showed good virological suppression rates of second-line LPV/r and NRTI regimens, even in patients with significant NRTI resistance. These trials demonstrated that without the use of a resistance test to decide which NRTIs to use in second-line therapy with PI/r, virological outcomes were good and similar to a boosted PI + RAL regimen. In addition, those patients with more extensive NRTI resistance at first-line failure were more likely to achieve virological suppression in second-line therapy.73

    LPV/r, ritonavir-boosted lopinavir; NRTI, nucleoside reverse transcriptase inhibitor; PI, protease inhibitor; RAL, raltegravir.